Ethano-anthracenes

ABSTRACT

9 - FORMYL -9:10 DIHYDRO - 9:10 -ETHANO - (1:2)ANTHRACENES ARE VALUABLE INTERMEDIATES FOR THE PREPARATION OF 9-R-METHYL - 9:10-ETHANO-(1:2)-ANTHRACENES, WHEREIN R IS A SUBSTITUTED OR UNSUBSTITUTED AMINO GROUP, AS WELL AS OF THEIR QUATERNARY AMMONIUM DERVATIVES AND SALTS, WHICH COMPOUNDS, ESPECIALLY THE AMINES AND THEIR THERAPEUTICALLY ACCEPTABLE SALTS; DISPLAY AN INHIBITORY ACTION ON THE CENTRAL NERVOUS SYSTEM CHARACTERIZED BY AN ANTAGONISM TOWARDS PSYCHOMOTORIC SUBSTANCES SUCH FOR EXAMPLE, AS MESCALIN, AND INHIBIT THE TRANSMISSION OF SPINAL REFLEXES AND CAN THEREFORE BE USED AS TRANQUILIZERS.

United States Patent 1 3,632,653 ETHANO-ANTHRACENES Paul Schmidt,Therwil, Max Wilhelm, Allschwil, and Kurt Eichenberger, Therwil,Switzerland, assignors to Ciba Corporation, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 541,979, Apr.12, 1966, now Patent No. 3,399,201, which is a continuation-in-part ofapplication Ser. No. 404,904, Oct. 19, 1964, which in turn is acontinuationin-part of applications Ser. No. 151,198, Nov. 9, 1961, andSer. No. 512,201, Dec. 7, 1965. This application Sept. 26, 1967, Ser.No. 670,752

Claims priority, application Switzerland, Nov. 29, 1960, 13,359/60; Oct.10, 1961, 11,710/61; Nov. 1, 1963, 13,434/63; Dec. 23, 1964, 16,637/64;Nov. 24 1965, 16,177/65; Dec. 10, 1965, 17,086/65 Int. Cl. C07c 47/52US. Cl. 260-599 3 Claims ABSTRACT OF THE DISCLOSURE 9 formyl 9:10dihydro 9:10 ethano (1:2)- anthracenes are valuable intermediates forthe preparation of 9-R-methy19:10-dihydro-9:lO-ethano-(l:2)-anthracenes, wherein R is a substitutedor unsubstituted amino group, as well as of their quaternary ammoniumderivatives and salts, which compounds, especially the amines and theirtherapeutically acceptable salts; display an inhibitory action on thecentral nervous system characterized by an antagonism towardspsychomotoric substances such, for example, as mescalin, and inhibit thetransmission of spinal reflexes and can therefore be used astranquilizers.

CROSS-REFERENCES This is a continuation-in-part application of our 00-pending application Ser. No. 541,979, filed Apr. 12, 1966, and now Pat.No. 3,399,201, which is a continuation-inpart of our application Ser.No. 404,904, filed Oct. 19, 1964, and now abandoned which in turn is acontinuationin-part of our application Ser. No. 151,198, filed Nov. 9,1961, and now abandoned, and of our application Ser. No. 512,201, filedDec. 7, 1965, and now abandoned.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 9-formyl-9:10-dihydro-9zl0-ethano-(1:2)-anthracenes which are valuable intermediates for the preparationof 9-R-methyl-9:10-dihydro-9:IO-ethano- (112)-anthracenes wherein R is asubstituted or unsubstituted amino group, as well as of their quaternaryammonium derivatives and salts, which compounds, especially the aminesand their therapeutically acceptable salts, display an inhibitory actionon the central nervous system characterized by an antagonism towardspsychomotoric substances such, for example, as mescaline, and inhibitthe transmission of spinal reflexes and can there.- fore be used astranquilizers. The 9-formyl compounds are converted into the9-aminomethyl compounds by reaction with the corresponding amine andsimultaneous or subsequent reduction.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the9-aminomethyl-9:10-dihydro-9:10-ethano-(1:2)- anthracenes containing thenucleus of the formula the amino group of the amino-alkyl residue may beunsubstituted, but it is preferably monosubstituted or disubstituted.Particularly suitable substituents are lower hydrocarbon residues whichmay be interrupted by hetero atoms such as oxygen, sulphur or nitrogen,and/or may be substituted by free hydroXyl, amino or mercapto groups orby halogen atoms such as fluorine, chlorine, bromine or iodine. As lowerhydrocarbon residues there may be mentioned above all: Lower alkyl oralkenyl groups such as methyl, ethyl, propyl, or isopropyl; straight orbranched butyl, pentyl, hexyl, or heptyl radicals bound in any desiredposition; allyl or methallyl radicals; unsubstituted oralkyl-substituted cycloakyl 0r cycloalkenyl groups such as cyclopentyl,cyclohexyl, cycloheptyl, cyclopentyl, cyclohexenyl groups; unsubstitutedor alkyl-substituted cycloalkyl-alkyl or cycloalkenyl-alkyl groups suchas cyclopentylor cyclohexenyl-methyl, -ethyl or -propyl groups; aralkylor aralkenyl such as phenylmethyl, -ethyl, vinyl or propyl groups; oraryl, more especially phenyl radicals; or alkylene or alkenylene groupssuch, for example as butylene-(1z4), pentylene (1:5),1:5-dimethylpentylene-( 1:5), hexylene-(1z6) and hexylene-( 1:5).Residues of this kind interrupted by hetero atoms are, for example,alkoxyalkyl or oxa-cycloalkyl-alkyl groups such as methoxyethyl,ethoxyethyl propoxyethyl, butoxyethyl, methoxypropyl,methoxyethoxyethyl, tetrahydrofurylmethyl, methylmercaptoethyl, oxa-,azaor thia-alkylene or -alkenylene residues such as 3-aza-, oxaorthia-pentylene-(1:5 3-aza-hexylene- (1:6),1:5-dimethyl-3-aza-pentylene-(1 :5), 3 methyl 3- aza-pentylene-( 1:5),or 3-hydroxyethyl-3-aza-pentylene- (1:5). The amino group is above all amonoor di-lower alkyl-amino group such as the methylamino, ethylamino,n-butylamino, dimethylamino, diethylamino, dipropylamino,N-methyl-N-ethylamino group, or an N lower alkyl-N-cycloalkylamino groupsuch as the N-methyl-N- cyclopentyl or -cy-clohexyl group; or apyrrolidino, piperi dino, morpholino or thia-morpholino group such aspyrrolidino, piperidino, morpholino, piperazino, N-methyl-, N-ethylorN-fi-hydroxyethyl-piperazino group.

The fourth substituent on a quaternary ammonium group is above all alower alkyl or alkenyl group such as a methyl, ethyl, allyl, propyl orbenzyl group or a phenoxy-lower alkyl such as the phenoxyethyl group.

The alkylene residue which connects the aforementioned amino group withthe anthracene nucleus is above all of lower unbranched or branchedalkylene group which preferably contains 1 to 4 carbon atoms such, forexample as a methylene, ethylene-(1 :2), propylene-(1:2),

propylene-(1:3), butylene-(1:2), butylene-(1z3), butylone-(2:3) orbutylene-(1z4) residue.

The new compounds can be further substituted, for example, in positions1 to 8 of the anthracene ring or on other aromatic rings by lower alkyl,alkoxy, alkenyloxy or alkylmercapto groups, by halogen atoms such as fluorine, chlorine, bromine or iodine or by the pseudohalogentrifluoromethyl, by alkylsulphonyl, alkanoyl, nitro or amino groups, andin this connection there may be mentioned as alkyl groups, for example,methyl, ethyl propyl, isopropyl, butyl, isobutyl, or tertiary butyl; asalkoxy or alkenyloxy groups the methoxy, ethoxy, allyloxy ormethylenedioxy group; as alkylmercapto the methylmercapto orethylmercapto group; and as alkanoyl groups above all the acetylpropionyl or butyryl residue. In position 10 the new compounds maycontain above all an aliphatic hydrocarbon residue such as one of theabovementioned lower alkyl or alkenyl groups, or a halogen atom.

The new compounds have valuable pharmacological properties; inter aliathey display an inhibitory action on the central nervous systemcharacterized by an antagonism towards psychomotoric substances such,for example, as mescalin, and inhibit the transmission of spinalreflexes; and they can therefore be used as tranquilizers in human andveterinary medicine. They are also suitable as additives to animalfodder, since they bring about a better intake.

In addition, the new compounds may be used as starting material orintermediates for the preparation of other valuable compounds.

Of special value are the 9-aminomethyl and 9-aminopropyl 9:lO-dihydro-9: IO-ethano-(l:2)-anthracenes and their salts and amongstthem especially those in which the amino group is secondary or tertiary,preferably being a monoor di-lower alkyl amino or cycloalkylamino,pyrrolidino, piperidino, morpholino, piperazino, N-methylpiperazino,N-ethylpiperazino or N-fl-hydroxy-ethylpiperazino group.

Special mention deserve the compounds of the formula (iJH -A (JET-C H1-CH2A. A \y and and their salts, in which A represents a secondary ortertiary amino group, more especially one of the last-mentioned aminogroups, especially a dimethylamino or methylamino group. Of primaryimportance are and their salts.

The new compounds are prepared by as such known methods.

Thus, for example, a residue convertible into an aminoalkyl orammonium-alkyl group, present in position 9 of a9:l0-dihydro-9:10-alkano-(1:2)-anthracene may be so converted. A residueconvertible into an aminoalkyl or ammoniumalkyl group is for example onewhich is convertible into an aminoalkyl group by reduction, for examplecarbamyl, or carbamylalkyl groups which can be reduced in conventionalmanner, advantageously with lithium-aluminum hydride or a similarreducing agent for amides, to form the corresponding aminoalkyl groups.

Similarly, nitroalkyl, nitroalkenyl, cyano or cyanoalkyl groups can bereduced to the corresponding aminoalkyl groups, the reduction of saidgroupings being carried out with the use of a conventional agent such,for example as activated hydrogen, more especially catalyticallyactivated hydrogen. Catalysts particularly suitable for this purpose areRupe or Raney nickel, or platinum or palladium catalysts.

Further groups that can be reduced to amino-alkyl groups are iminoalkylresidues or the corresponding amiuo-hydroxy-alkyl residues which can beconverted into the aminoalkyl residues with the use of a conventionalreducing agent, primarily a metal hydride, for example a di-light metalhydride, such as alkali metal borohydride, or catalytically activatedhydrogen, forwhich purpose platinum oxide and Raney nickel areespecially suitable catalysts. As iminoalkyl residues there aresuitable, apart from the usual Schiifs bases, also hydroxyimino-alkylgroups.

According to another process the 9:lO-ethan0-(l:2) residue is introducedin conventional manner into a 9-ami- 4 V noalkyl-anthracene, or into aquaternary ammonium derivative or a salt thereof, advantageously withthe use of ethylene, by the Diels-Alder method; depending on thereactivit of the anthracene compound this reaction may have to becarried out at an elevated temperature and/or under superatmosphericpressure and/or in the presence of a catalyst.

In a resulting primary, secondary or tertiary amino group furthernitrogen substituents may be introduced in known manner, for example bytreatment with a reactive ester, for example one of those mentionedabove, or with a corresponding alcohol, or by reductive alkylation withthe use of an appropriate carbonyl compound or by acylation withcarboxylic acids or their functional derivatives and reduction of theobtained N-acyl compounds.

Further-more, substituents may be introduced into the benzene nuclei,such as nitro groups, which may be effected by nitration. substituentspresent in the molecule can be converted in the conventional manner, forexample nitro groups on the aromatic residues may be reduced to aminogroups.

The invention further includes any variant of the present process inwhich an intermediate obtained at any stage of the process is used asstarting material and/or the remaining step or steps is/ are carriedout; or the process is discontinued at any stage thereof; or in which astarting material is formed in the course of the reaction, or used inthe form of a quaternary ammonium compound or a salt thereof. Thus, forexample, the starting material may be a9-oxoalkyl-9:1-0-dihydro-9:10-ethano-(1:2)-anthracene, for example a9-formyl or 9aformylalkyl compound, which is treated under suitablereducing conditions, for example those mentioned above for reducingiminoalkyl groups, with ammonia or with a primary or secondary amine,which procedure yields as intermediate one of the aforementionediminohydroxy or aminohydroxy compounds.

The aforementioned reactions are carried out in the usual manner in thepresence or absence of diluents, condensing agents and/ or catalysts, atroom temperature or a lower or higher temperature, if desired undersuperatmospheric pressure.

The starting materials are known or can be prepared by known methods.Any new starting materials used are likewise included in the invention.

Depending on the reaction conditions and starting material used the newcompounds are obtained in the free form or in the form of salts thereof.The salts of the new compounds can be converted in known manner into thefree compounds, for example acid addition salts by reaction with a basicagent. On the other hand, a resulting free base may form salts withinorganic or organic acids. Acid addition salts are preferablymanufactured with therapeutically useful acids, for example a hydrohalicacid such as hydrochloric or hydrobromic acid, perchloric, nitric orthiocyanic acid, a sulphuric or phosphoric acid, or an organic acid suchas formic, acetic, propionic, glycollic, lactic, pyruvic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic,hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-amino-benzoic,4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4aminosalicylic, 2 phenoxybenzoic, 2 acetoxybenzoic, methanesulphonic,ethanesulphonic, hydroxyethanesulphonic, benzenesulphonic,para-toluene-sulphonic, naphthalenesulphonic or sulphanilic acid;methionine, tryptophan, lysine or arginine. The salts may be monosaltsor polysalts.

Quaternary ammonium salts may also be converted into the ammoniumhydroxides, for example by treatment of an ammonium halide with freshlyprecipitated silver oxide, or by treating an ammonium sulphate withbarium hydroxide solution, or with the use of a basic ionexchanger, andfrom the resulting ammonium hydroxide other ammonium salts can beprepared by reaction with an acid, for example one of those mentionedabove. If

desired, this exchange may also be carried out directly with the use ofa suitable ion-exchanger.

The new compounds are intended to be used as medicaments in the form ofpharmaceutical preparations containing them in conjunction with apharmaceutical organic or inorganic, solid or liquid excipient suitablefor enteral (for example oral) or parenteral administration. Suitableexcipients are substances that do not react with the new compounds such,for example, as water, gelatine, lactose, starch, magnesium stearate,talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols,cholesterol or other known medicinal excipients. The pharmaceuticalpreparations may be, for example, tablets, dragees or capsules, or inliquid form solutions, suspensions or emulsions. They may be sterilisedand/or may contain assistants such as preserving, stabilising, wettingor emulsifying agents, salts for regulating the osmotic pressure orbuffers. The dosage of the new compounds may vary according to theparticular compound and the particular needs of the patient. Usually, itis in the range of 25-500' mg. daily, for example between 75 and 300 mg;the dose may be divided and thus administered twice or three times aday. They may also contain other therapeutically valuable substances.

The new compounds may also be used in veterinary medicine, for examplein one of the forms mentioned above, or in the raising and feeding ofanimals in the form of fodders or as additives to animal fodder, forexample in admixture with the conventional extenders and diluents andfeeding stutfs respectively.

The following examples illustrate the invention.

EXAMPLE 1 A solution of 9.0 grams of 9:10-dihydro-9zl0-ethano-(l:2)-anthracene-(9)-carboxylic acid diethylamide in 50 cc. oftetrahydrofuran is stirred dropwise at room temperature into asuspension of 2.5 grams of lithiumaluminium hydride in 100 cc. oftetrahydrofuran. The mixture is heated for 3 hours at the boil and thencooled in ice. The organo-metal complexes and the excess oflithium-aluminium hydride are decomposed by carefully dropping in 2.5cc. of water, 2.5 cc. of sodium hydroxide solution of strength and 7.5cc. of water. The granular precipitate formed is filtered off and thesolvent is evaporated, to yield 9-diethylamino-methyl-9:IO-dihydro-9:IO-ethano-(l:2)-anthracene of the formula which melts at 112 to 115 C.after having been recrystallised from ethanol. Its hydrochloride meltsat 243 to 245 C.

The 9:10 dihydro-9:10-ethano-(1:2)-anthracene-(9)- carboxylic aciddiethylamide used as starting material is prepared in the followingmanner:

A mixture of 10.0 grams of 9:10-dihydr0-9:10-ethano-(1:2)-anthracene-(9)-carboxylic acid and 100 cc. of thionyl chloride isrefluxed for 6 hours; the thionyl chloride is then evaporated to leavean oil which crystallises When left to itself for some time.Recrystallisation from petroleum ether yields the9:l0-dihydro-9:10-ethano- 6 (1:2)-anthracene-(9)-carboxylic acidchloride of the formula in crystals melting at 72 to 75 C.

10.0 grams of diethyl'amine in 25 cc. of benzene are vigorously stirreddropwise at room temperature into 5 grams of the acid chloride in 50 cc.of benzene. The mixture is stirred for 2 hours at 40 C. and thenextracted with water. On evaporation of the benzene an oil remains whichcrystallises slowly. Recrystallisation from aqueous methanol yields the9:l0-dihydro-9-:l0-ethano-(l:2)- anthracene-(9)-carboxylic aciddiethylamide of the formula in crystals melting at 108 to 109 C.

EXAMPLE 2 A mixture of 10.0 grams of 9:10-dihydro-9: lO-ethano-(1:2)-anthracene-(9)-aldehyde, 6.0 grams of fi-phenylethyl-amine and 150cc. of benzene is boiled for 2 hours with the use of a water s parator,whereupon the benzene is evaporated in vacuo. the residue is dissolvedin 200 cc. of ethyl acetate, treated with 2 grams of Raney nickel andhydrogenated at room temperature under atmospheric pressure. Thecatalyst is then filtered off and the solvent evaporated, the residuebeing treated with cc. of 2 N- hydrochloric acid, whereuponcrystallisation sets in to yield the 9-(fi-phenylethylaminomethyl) 9: 10dihydro- 9: 10 ethano (1:2) anthracene hydrochloride of the formulawhich melts at 253 to 255 C. after having been recrystallised fromethanol-l-ether.

The 9:10 dihydro-9:10-ethano-(l:2)anthracene-(9)- aldehyde used asstarting material is prepared as follows:

A solution of 50 grams of anthracene-(9)-aldehyde in 200 cc. ofdimethylformamide is heated in an autoclave with ethylene to 170 C. thewhole is cooled after 24 hours, and the solvent is evaporated in awater-jet vacuum. The residue is dissolved in a small amount ofchloroform. On addition or" ethanol the 9: l0-dihyclro-9zl0-ethano-(l:2)-anthracene-(9)-aldehyde of the formula crystallises in theform of prisms melting at 106 to 107 C.

EXAMPLE 3 A solution of 10.0 grams of 9:10-dihydro-9z10-ethano-(1:2)-anthracene-(9)aldehyde and 5.0 grams of n-butylamine in cc. ofbenzene is boiled for 2 hours with the use of a water separator and thenevaporated to dryness. The residue is dissolved in 100 cc. of ethanol,treated with 2.0 grams of Raney nickel and hydrogenated at roomtemperature under atmospheric pressure. When hydrogen is no longer beingconsumed, the catalyst is filtered oh. and the solvent evaporated, toyield 9-(n-butyl-amino-methyl)-9:10-dihydro-9:10-ethano-(1:2)-anthracene of the formula(]3HgNH-CH2CH2CHZCH3 which melts at 76 to 78 C. after having beenrecrystallised from ethanol.

EXAMPLE 4 A solution of 10 grams of 9:l0 dihydro-9:l0-ethano-(1:2)-anthracene-(9)-aldehyde and 10 grams of monomethylamine in 100 cc.of ethanol is heated at 80 C. for 4 hours in an autoclave. The reactionmixture is then evaporated to dryness under reduced pressure to leave acrystalline residue which is dissolved in 150 cc. of ethanol and, afterthe addition of 2 grams of Raney nickel, hy drogenated at 40 C. underatmospheric pressure. When the absorption of hydrogen has subsided, thecatalyst is filtered off and the filtrate evaporated under reducedpressure. An oil remains which is covered with 100 cc. of 2 N-hydrochloric acid. The 9-methylamino-methyl-9:lO-dihydro-9:10-ethanol-(1:2)-anthracene hydrochloride of the formulacrystallizes immediately; after crystallization from methanol it meltsat 320322 C.

EXAMPLE A mixture of grams of 9-rnethylamino-methyl-9z10-dihydro-9:IO-ethano-(l:2)-anthracene, 4 cc. of aqueous formaldehydesolution of 30% strength and 50 cc. of formic acid is heated at 90 C.for 5 hours. After cooling the reaction mixture is rendered alkaline bythe addition of 2 N-sodium hydroxide solution. The oil which hasseparated is extracted with methylene chloride and the extractevaporated. There remains 9-dimethylamino-methyl- 9: 10-dihydro-9:10-ethano-(l:2)-anthracene of the formula which melts at 78-80 C. aftercrystallization from ethanol; its hydrochloride melts at 233-234 C. Inan analogous manner from 9-(n-butylamino-methyl)-9:10-dihydro-9:10-ethano-(1:2)-anthracene there is obtained 9 (N methyl N nbutylamino methyl) 9:10- dihydro-9z10-ethano-(1:2)-anthracene melting at257 C.

hydrochloride.

EXAMPLE 6 A solution of 17.8 grams of N-acetyl-9-methylaminomethyl 9:10dihydro 9:10 ethano (1:2) anthracene in 50 cc. of tetrahydrofuran isadded dropwise with stirring, to 4 grams of lithium-aluminium hydride in100 cc. of tetrahydrofuran. The mixture is then stirred for 2 hours at50 C. 4 cc. of water, 4 cc. of sodium hydroxide solution of strength and12 cc. of water are then added to the reaction mixture, the precipitateformed is filtered with suction and the filtrate evaporated to drynessunder reduced pressure to yield 9-(methyl-ethylaminomethyl) 9:10 dihydro9:10 ethano (1:2) anthracene of the formula CH2-N/ a OW which melts at77-79 C. after crystallization from methanol; its hydrochloride melts at235236 C.

The N acetyl 9 methylamino methyl 9:10- dihydro 9:10 ethanol (1:2)anthracene used as starting material may be prepared in the conventionalmanner be acetylating 9 methylamino 9: 10 dihydro- 9: 10 ethano (1:2)anthracene with acetyl chloride in pyridine. The compound melts at 128C. after recrystallization from ethanol.

EXAMPLE 7 CHz-NH:

precipitating in the form of crystals melting as 3133l5 EXAMPLE 8Ethylene is introduced into a solution of 10 grams of 9 dimethylaminomethyl anthracene in 300 cc. of benzene in an autoclave up to 45atmospheres gauge pressure, and the mixture is then heated for 12 hoursat 170 C.

After the reaction has ceased, the benzene solution is extracted with 2N-hydrochloric acid, the acidic extract rendered alkaline by theaddition of sodium hydroxide solution, and the precipitated =baseextracted with methyl ene chloride. After drying and evaporation of thesolvent there remains 9-dimethyla-mino-methyl-9:10-dihydro-9:10-e'thano-(1:2)-anthracene of the formula which is converted into itshydrochloride of M.P. 234 C. by the addition of ethanolic hydrochloricacid and diethyl ether.

The 9 dimethylamino methyl anthracene used as starting material may beprepared as follows:

20 grams of 9-chloromethyl-anthracene are heated with 10 grams ofdimethylamine in cc. of ethanol for 5 hours in an autoclave at 100 C.The reaction mixture is then evaporated to dryness under reducedpressure, the residue dissolved in ether and the solution extracted with2 N-sodiurn hydroxide solution. After drying and evaporation of theethereal solution there is obtained 9-dimethylamino-methyl-anthracenewhich after crystallization from ethanol melts at 6566 C. i

9 EXAMPLE 9 12 grams of[3-[9210-dihydr0-9:l0-ethano-(l:2)-9-anthrylJpropionic aciddimethylamide in 50 cc. of tetrahydrofuran are added dropwise withstirring at room temperature to a suspension of 3.5 grams oflithium-aluminium-hydride in 100cc. of dry tetrahydrofuran; the mixtureis then boiled under reflux for 2 hours. 4 cc. of water and 10 cc. ofsodium hydroxide solution of 15% strength are then added dropwise whilecooling with ice, and the precipitate which settles out is filtered. Thefiltrate is evaporated to dryness under reduced pressure, the oilyresidue dissolved in ether and the ether solution extracted With 2N-hydrochloric acid. The acidic solution is rendered alkaline by theaddition of 10 N-sodium hydroxide solution and the precipitated baseextracted with ether. After drying and evaporation of the extract thereis obtained 9-' -din1ethylamino-pr0pyl 9:10 dihydro 9:lethano-(1:2)-anthracene of the formula which melts at 8890 C. aftersublimation; its hydrochloride melts at 205206 C.

The -[9: l0-dihydro-9: -ethano-( 1 :2) -9-anthryl] -propionic aciddimethylamide used as starting material may be prepared as follows:

A solution of 10 grams of [3-(9-anthryl)-propionic acid [prepared asdescribed by F. H. C. Stewart, Australian Journal of Chem. 13, 483(1960)] in 200 cc. of dimethylformamide is saturated with ethylene andthe mixture heated in an autoclave for 24 hours at 170 C. After cooling,500 cc. of water are added the precipitate formed filtered otf. Theprecipitate is recrystallized from ethanol to yield ;3-[9:l0-dihydro-9:IO-ethano-(l:2)-9-anthryl]- propionic acid of theformula on on coon in the form of crystals melting at 218-219 C.

10 grams of the above acid are boiled with 500 cc. of thionyl chloridefor 4 hours and the mixture evaporated to dryness under reduced pressureto yield a crystalline residue which is dissolved in 50 cc. of benzene.To this solution there is added dropwise at room temperature, withstirring, a solution of 5 grams of dimethylamine in 50cc. of benzene.After 2 hours 100cc. of water are added, the benzene layer separated,dried over sodium sulphate and evaporated. There remains crystalline [3-[9: 10 dihydro-9:10-ethano-(1:2)-9-anthryl] propionic acid dimethylamidewhich can be used without further purification.

EXAMPLE 10 A solution of 14.0 grams of 2-chloro-anthracene-(9)-aldehydein 200 cc. of dimethyl-formamide is saturated with ethylene and thenheated in an autoclave for 24 hours at 170 C. The dimethylformamide isthen distilled off in vacuo. A viscous oil remains behind which isdissolved in 100 cc. of ethanol; after the addition of 10 grams ofmonomethylamine, the reaction mixture is heated in a bomb tube for 4hours at 90 C. The solution is evaporated to dryness, the residuedissolved in 200 cc. of ethanol and, after the addition of 2 grams ofRaney nickel, hydrogenated under 5 atmospheres gauge pressure. Afterfiltering off the catalyst, the reaction mixture is evaporated todryness under reduced pressure. The residue is boiled with 100 cc. of 2N-hydrochloric acid and the hydrochloricacid solution is separated off.0n cooling, an oil separates which crystallizes after being allowed tostand for some time. There is obtained2-chloro-9-methylaminomethyl-9:10-dihydro-9:10-ethano-(1:2)-anthracenehydrochloride of the formula in the form of white crystals which melt at223-226 C. after crystallization from water.

The 2-chloro-anthracene-(9)-aldehyde used as starting material may beprepared as follows:

A mixture of 42 grams of 2-chloro-anthracene, 54 grams ofN-methyl-formamide, 60 grams of phosphorus oxychloride and 40 cc. ofdichloro-benzene is heated for 2 hours at 95 C. with stirring. Asolution of 280 grams of crystalline sodium acetate in 500 cc. of wateris then added. A precipitate settles out which is filtered olf andboiled with ethanol. The hot ethanol solution is filtered. On coolingthe filtrate, 2-chloroanthracene-(9)-aldehyde separates in the form ofyellow needles which melt at 148-150 C. after recrystallization fromglacial acetic acid.

EXAMPLE 11 A solution of 5.0 grams of dimethylamine in 50 cc. of benzeneis added dropwise and with stirring to 4.0 grams of1:5-dichloro-9:10-dihydro-9:10-ethano-(1:2)- anthracene-9-carboxylicacid chloride in 50 cc. of benzene at room temperature. After 2 hours,cc. of water are added and the benzene layer is evaporated to drynessunder reduced pressure. The residue is dissolved in 50 cc. of absolutetetrahydrofuran and the resulting solution added dropwise and withstirring to a mixture of 2.0 grams of lithium aluminium hydride and 50cc. of tetrahydrofuran. The mixture is heated to the boil for 2 hoursand then decomposed by the addition of water and sodium hydroxidesolution of 15% strength. After filtering ofi the precipitate which hassettled out and evaporating the filtrate, an oil remains which isdissolved in 10 cc. of ethanol. The solution is treated with 0.5 cc. of10 N-ethanolic hydrochloric acid and the hydrochloride formed isprecipitated by the addition of diethyl ether. There is obtained1:5-dichloro-9-dimethylamino-methyl 9:10dihydro-9:l0-ethano-(l:2)anthracene-hydrochloride of the formula(lJHz'N(CH3)2HC1 \V in the form of crystals melting at 158l62 C.

The 1:5 dichloro-9: 10-dihydro-9: 10-ethano-(1:2)-anthracene9carboxylicacid chloride used as starting mate rial may be prepared as follows:

A solution of 12 grams of 1:5-dichloro-anthracene- (9)-carboxylic acidin 200 cc. of dimethyl-forrnamide is saturated with ethylene and thenheated for 24 hours at C. in an autoclave. The residue which remainsafter the solution has been evaporated under reduced pressure isdissolved in 2 N-sodium hydroxide solution and filtered through carbon.On acidification of the solution crude1:5-dichloro-9:l0-dihydr0-9:10ethano-(1:2)- anthracene-9-carboxylic acidprecipitates which is filtered off and dried. 10 grams of this acid areboiled for 2 hours with 200 cc. of thionyl chloride. When the solutionhas been evaporated there remains an oil which crystallizes slowly.After recrystallization from petroleum ether there is obtained1:5-dichloro-9:IO-dihydro- 9: IO-ethano-(l:2)-anthracene-9-carboxylicacid chloride of the formula melting at 132-135 C.

EXAMPLE 12 12 g. of [3-[9:10-dihydro-9:10-ethano-(1:2)-anthryl]-propionyl chloride in 75 ml. of methylenechloride are stirred dropwiseinto a solution of 7 g. of fi-hydroxyethyl-piperazine in 75 ml. ofmethylenechloride. The whole is stirred for 3 hours at room temperature,and the precipitate formed is then filtered off. The filtrate isevaporated and the residue dissolved in 2 N-hydrochloric acid andextracted with ether. The acidic extract is alkalinized and extractedwith methylenchloride. The methylenechloride is separated, dried oversodium sulfate and evaporated. The residue, (B-[9:10-dihydro-9:10-ethano (1:2) anthryl1propionic acid-N-([3-hydroxyethyl)-piperazide), isdissolved in 100 ml. of absolute tetrahydrofuran. This solution is addeddropwise to a suspension of 7.5 g. of lithium aluminium hydride in 100ml. of tetrahydrofuran, and the whole is heated for 2 hours at 50 C.,then cooled, whereupon 8 ml. of water, 8 ml. of 15% sodium hydroxidesolution and 24 ml. of water are successively dropped in. The resultingprecipitate is filtered off and the filtrate is evaporated under vacuum,to leave an oily residue, namely (9-[-(N'-hydroxyethyl-piperazino)-propyl] 9:10 dihydro- 9:IO-ethano-(l:2)-anthracene), which is dissolved in 100 ml. of ethanol.On addition of 10 ml. of 10% alcoholic hydrochloric acid a precipitateis obtained which is recrystallized from methanol, to yield9-['y-(N-hydroxyethyl-piperazino)-propyl]-9:IO-dihydro 9:10 ethano-(122) -anthracene dihydrochloride of the formula in white crystalsmelting at 266 to 268 C.

This product may be incorporated, for example, in tablets of thefollowing composition:

EXAMPLE 13 34 g. of B-[9,10-dihydro-9,l-ethano-(l,2)-9-anthryl]-propionic acid monomethylamide in 150 ml. of absolute tetrahydrofuranare stirred dropwise at room temperature into a suspension of g. oflithium-aluminium hydride in 250 ml. of absolute tetrahydrofuran, andthe mixture is heated for 3 hours at 60 C. and then cooled to 10 C. 10ml. of water and 10 ml. of 15% sodium hydroxide solution are thendropped in and the precipitate formed is filtered off. The filtrate isevaporated under vacuum, to leave an oil which is dissolved in 50 ml. ofethanol. On addition of 10 N-ethanolic hydro 3 9,10dihydro-9,10-ethano-(1,2)-anthracence hydrochloride of the formulaprecipitates in the form of white crystals which melt at 230 to 232 C.after recrystallization from isopropanol.

The 13-[9,10-dihydro-9,10-ethano-(1,2)-9-anthryl]-propionic acidmonomethylamide used as starting material can be prepared in thefollowing manner:

While cooling a solution of 50.0 g. of B-[9,10 dihydro-9,10-ethano-(1,2)-9-anthryl]-propionylchloride in /2 liter ofmethylenechloride about 20 g. of monomethylamine is introduced into itin the course of one hour. 200 ml. of water are then added, themethylenechloride layer is separated, dried over sodium sulphate and thesolvent is distilled off, to yield fi-[9,10-dihydro-9,l0-ethano-(1,2)-9-anthryl]-propionic acid monomethylarnide which melts at 158 to 161 C.after recrystallization from a mixture of methylenechloride+petroleumether.

Tablets, each containing 25 mg. of active principle, can be prepared,for example, from the following ingredients:

Mg. 9 (7 methylamino propy) 9,10 dihydrm 9,10-ethano 1,2-anthracenehydrochloride 25 Lactose 35 Wheat starch 44.4 Colloidal silicic acid 6Magnesium stearate 0.6 Talc 9 120.0 EXAMPLE 14 A solution of 6.8 g. of13-[l0-chloro-9,10-dihydro-9,l0- ethano-(l,2)-9-anthryl]-propionic aciddimethylamide in 40 ml. of absolute tetrahydrofuran is stirred dropwiseinto a suspension of 2.5 g. of lithium-aluminium hydride in 60 ml. ofabsolute tetrahydrofuran. The mixture is then heated for 3 hours at 70C., cooled to room temperature and 12 ml. of water are cautiously added.The precipitate formed is filtered 01f, and the filtrate evaporatedunder vacuum, the oily residue dissolved in ether and the etherealsolution is extracted with 2 N-hydrochloric acid. The acid solution isalkalinized with 10 N-sodium hydroxide solution and the precipitatedbase is extracted with ether. The extract is dried and evaporated, toleave 9-y-dimethylaminopropyl-l0-chloro-9,10 dihydro 9,10- ethano-(l,2)-anthracene of the formula CHzCHgOHgN A w. (ll/Q 3.

13 9-hydroxymethy1-10-ch1oroanthracene melting at 203- 205 C.

26 grams of 9-hydroxymethyl-10-chloroanthracene are mixed with 14 g. ofthionylchloride in 100 ml. of dioxan and refluxed for 2 hours. Aftercooling 9-chloromethyl-10- chloroanthracene precipitates in crystallineform. After recrystallization from hexane the compound melts at 168- 170C.

16 grams of malonic acid diethyl ester are added to a suspension of 2.5g. of sodium hydride in 300 ml. of benzene and the whole is heated for 2hours at 80 C. 24 grams of 9-chloromethyl-10-chloroanthracene are addedand the mixture is refluxed for 7 hours. 200 ml. of Water are then addedto room temperature and the benzene layer is separated. Afterevaporation of the solvent 1-(10-chloro-9-anthryl)-2,2-ethanedicarboxylic acid diethyl ester is obtained;after recrystallization from isopropanol it melts at 88-93 C.

When 27 g. of this ester are boiled in a solution of 80 ml. of 2N-sodium hydroxide solution and 100 ml. of alcohol and then acidifiedwith N-hydrochloric acid, there is obtained the1-(10-chloro-9-anthryl)-ethane-2,2- dicarboxylic acid (melting at 216C.) which on heating to 220 C. gives rise tofl-(10-chloro-9-anthryl)-propionic acid by decarboxylation; thiscompound melts at 190- 194 C. after recrystallization fromdioxan+petroleum ether.

A solution of 12 g. of fl-(10-chloro-9-anthryl)-propionic acid in 250 g.of toluene is heated in an autoclave with ethylene for 20 hours at 170C. On cooling, crystalline B [10 chloro 9,10 4 dihydro 9,10 ethano(1,2)-9- anthryl]-propionic acid melting at 280 C. is obtained.

8 grams of this acid are heated for 2 hours with 80 ml. ofthionylchloride. On evaporation of the excess thionylchloride,;8-[10-chloro-9,10-dihydr0-9,l0-ethane-( 1,2)-9- anthryl]-pr0pi0nic acidchloride is obtained which melts at 145-150 C. after recrystallizationfrom hexane.

Dimethylamine is injected for one hour into a solution of 7.5 g. of theacid chloride in 75 ml. of benzene. The precipitate formed is filteredOE and th e filtrate evaporated under vacuum, to leave a residue whichis recrystallized from ether, to yieldB-[l0-chloro-9,10-dihydro-9,10-ethano-(1,2)-9-anthryl1-propionic aciddimethylamide in crystals melting at 143-147 C.

EXAMPLE 15 17 grams of B-[2-chloro-9,10-dihydro-9,10-ethano-(1,2)-9-anthryl] -propionic acid dimethylamide in 100 ml. of absolutetetrahydrofuran are stirred dropwise into a suspension of 5 g. oflithium-aluminum hydride in 100 ml. of absolute tetrahydrofuran, and themixture is stirred for 5 hours at 60 C., then cooled and 20 ml. of waterare added. The precipitate formed is filtered ofif and the filtrateevaporated under vacuum, to leave an oil which is mixed with 2 ml. of 10N-hydrochloric acid in alcohol and ether, to yield 2-chloro-9-'-dimethylaminopropyl-9,10-dihydro-9,10-ethano-(1,2)-anthracenehydrochloride of the formula omomOmNwHm A C1 :HOl

which melts at 171-173 C. after recrystallization from isopropanol.

The B-[Z-chloro 9,10 dihydro-9,10-ethano-(1,2)-9- anthryl]-propionicacid dimethylamide used as starting 14 material is obtained by themethods described in Example 14 from 2-chloroanthracene-(9)-aldehyde via(a) 2-chloro-9-hydroxymethylanthracene (M.P.

(b) 2-chloro-9-chloromethylanthracene (M.P. 140- (c)1-(2-chloro-9-anth-ryl)-2-ethane-dicarboxy1ic acid diethyl ester (oil)(d) 1-(2-chloro-9-anthryl)-2-ethane-dicarboxylic acid (M.P. 210 C.)

(e) 3-[2-chloro-9,l0-dihydro-9,10-ethano-(l,2)-9- anthryl]-propionicacid (M.P. C.)

(f) 5- [2-chloro-9,10-dihydro-9,10-ethano-(1,2)-9

anthryl] -propionic acid chloride (oil) (g) B-[2-chloro-9,10-dihydro-9,10-ethano-( 1,2 -9- anthryl]-propionic aciddimethylamide (oil).

EXAMPLE 16 A solution of 30 g. of B-[3-chloro-9,10-dihydro-9,10-ethano-(1,2)-9-anthryl]-propionic acid dimethylamide in 200 ml. ofabsolute tetrahydrofuran is stirred dropwise under nitrogen into asuspension of 6 g. of lithiumaluminium hydride in 200 ml. of absolutetetrahydrofuran. The reaction mixture is refluxed for 2 hours, cooled,and 6 ml. of water, 6 ml. of sodium hydroxide solution of 15% strengthand 18 ml. of water are added. The whole is completely evaporated andthe residue dissolved in 200 ml. of 2 N -hydrochloric acid, the solutionextracted with ether and the residual aqueous phase is rendered clearlyalkaline with concentrated sodium hydroxide solution while being cooled,and extracted with ether. The ethereal extracts are dried over sodiumsulphate and evaporated to form an oily residue which is once moredissolved in ether and mixed with the calculated amount of maleic acidin ether, to yield a crystalline maleate of the formula which melts at154-156 C. after recrystallization from ethanol+ether.

The B-[3-chloro 9,10 dihydro-9,10-ethano-(l,2)-9- anthryl]-propionicacid dimethylamide used as starting material is obtained in oily formfrom B-(3-chloro-9- anthryl)-propionic acid (melting at 189-190 C.) byreaction with ethylene oxide to form fi-[3-chloro-9,10-dihydro-9,10-ethano (1,2) 9 anthrylJ-propionic acid (melting at 197199C.), conversion with thionylchloride into the acid chloride and reactionwith dimethylamine.

EXAMPLE 17 A solution of 25 g. of ,8-[3-chloro-9,10-dihydro-9,10-ethane-(1,2)-9-anthryl]-propionic acid monomethylamide in 200 ml. ofabsolute tetrahydrofuran is stirred dropwise under nitrogen into asuspension of 6 g. of lithium-aluminium hydride in 200 ml. of absolutetetrahydrofuran. The reaction mixture is refluxed for 2 hours, cooled,and 6 ml. of water, 6 ml. of sodium hydroxide solution of 15 strengthand 18 ml. of water are added. The batch is completely evaporated undervacuum, the residue dissolved in 500 ml. of 2 N-hydrochloric acid, thesolution extracted with ether and the aqueous residue rendereddistinctly alkaline with concentrated sodium hydroxide solution whilebeing cooled, and then extracted with ether. The ethereal extracts aredried over sodium sulphate and evaporated, to yield3-chloro-9-('y-monomethylaminopro- 15 pyl)-9,10-dihydro 9,10ethano-1,2-anthracene of the formula CH CH C H NHC Ha oil? a Thefi-[3-chloro 9,10 dihydro-9,l-ethano-(1,2)-9- anthryl1-propionic acidmonomethylamide used as start ing material is obtained in oily form frommethylamine as described in Example 16.

EXAMPLE 18 A solution of 23 g. of 2-chloro-9-methylaminornethyl-9,10-dihydro 9,10 ethano-(l,2)-anthracene (cf. Example in 100 ml. offormic acid and 10 ml. of formalin of 30% strength is heated for 4 hoursat 90 C. /2 liter of water is then added and the Whole is renderedalkaline with 10 N-sodium hydroxide solution. The precipitating oil isextracted With ether. The ether extract is dried and evaporated, toyield 2-chloro-9-dimethylamino methyl-9,10-dihydro 9,10ethano-(l,2)-anthracene of the formula (IJHQNKJHQ;

whose hydrochloride melts at 244-245 C.

EXAMPLE 19 7 grams of N-acetyl-2-chloro 9 ethylaminomethyl-9,10-dihydro9,10-ethano (1,2) anthracene in 50 ml. of absolutetetrahydrofuran are dropped into a suspension of 2 g. oflithium-aluminium hydride in 50 ml. of absolute tetrahydrofuran and thewhole is stirred for 4 hours at 50 C., then cooled to room temperature,and ml. of water are cautiously added. The precipitate formed isfiltered oif and the filtrate evaporated under vacuum to dryness, toleave an oil which is dissolved in 10 ml. of ethanol. On addition of 1.5ml. of 10 N-hydrochloric acid in alcohol and ether, the hydrochloride of2-chloro-9- diethylaminoethyl-9,IO-dihydro 9,10 ethano (1,2)- anthraceneof the formula EXAMPLE A mixture of 36 g. of 10-chloro 9,10dihydro9,10'-

ethano-(1,2)-9-anthracene aldehyde and a saturated ethanolic solution ofethylamine is heated in an autoclave for 5 hours at 80 C., whereupon thesolution is evaporated under vacuum.

The residue is dissolved in 250 ml. of ethanol, 5 g. of Raney nickel areadded, and the mixture is hydrogenated at room temperature. After thecatalyst has been filtered off and the solvent evaporated, there remains9-ethyl- 16 aminomethyl-lO-chloro 9,10 dihydro 9,10 ethanoanthracene ofthe formula which melts at 88-91 C. after recrystallization from hexane.The hydrochloride melts above 300 C.

EXAMPLE 21 A solution of 14 g. of N-acetyl-9-ethylaminomethyl-10-chloro-9,10 dihydro-9,10-ethano-( 1,2) anthracene in 50 ml. of absolutetetrahydrofuran is dropped into 5 g. of lithium-aluminium hydride in ml.of absolute tetrahydrofuran, and the batch is then heated for 4 hours at60 C., whereupon 20 ml. of water are cautiously added at roomtemperature. The precipitate formed is filtered off and the filtrateevaporated to dryness under vacuum, to yield 9diethylaminomethyl-10-chloro-9,10-dihydro- 9,l0-ethano-(1,2)-anthraceneof the formula H2N( 2H5)2 which melts at 116-118 C. afterrecrystallization from ethanol. Its hydrochloride melts at ZOO-205 C.

The N-acetyl 9ethylaminomethyl-l0-chloro-9,IO-dihydro-9,l0-ethano-(1,2)-anthraceneused as starting material may be prepared by reacting9-ethylaminomethyl- 10-chloro 9,10 dihydro-9,10-ethano-(1,2)-anthracene(of. Example 18) with acetic anhydride at C. The compound melts at203-205 C.

EXAMPLE 22 13 grams of 9-dimethylaminomethyl-9,1O dihydro-9,10-ethano-(1,2)-anthracene are stirred into a mixture of 100 ml. ofconcentrated sulphuric acid and 10 ml. of concentrated nitric acid, andthe mixture is heated for 1 hour at 60 C., then poured over ice andrendered alkaline with 10 N-sodium hydroxide solution. On extractionwith methylenechloride, drying and evaporation, a solid residue isobtained which is recrystallized from alcohol, to yield 1,3,6trinitro-9-dimethylaminomethyl-9,10-dihydro-9,10-ethanol-(l,2)-anthracene of the formula IEO; CHg

A OZN y N0:

in yellow crystals melting at 183l84 C.

What is claimed is:

1. A compound selected from the group consisting of 9:10-dihydro-9:10ethano-(1:Z)-anthracene (9) aldehyde and 2-chloro-9:10'-dihydro 9:10ethano-(1:2)- anthracene- (9 -aldehyde.

2. A compound as claimed in claim 1, said compound being the 9:10dihydro-9:l0-ethano-(1:2)-anthracene- (9)-aldehyde.

3. A compound as claimed in claim 1, said compound 17 18 being the2-ch1oro-9z10-dihydr0 9:10 ethano-(1:2)- BERNARD HELFIN, PrimaryExaminer anthracene-(9)-aldehyde.

US. Cl. X.R.

References C'ted Except for Abstract and Summary of Invention on UNITEDSTATES PATENTS 5 p. 2, of spec. disclosure, identical to that of ParentPat. No.

1,717,567 6/1929 Kalischer et a1 260-599 2 1 f d t t t FOREIGN PATENTSequa e y C1'OSS-I6 6I6I1C6 1n paren pa en 947,946 1/1964 Great Britain260-599

